心脏手术后急性肾损伤(CSA-AKI)是常见的严重并发症，尚无有效治疗方法。申请者前期研究证实体外循环(CPB)时红细胞破坏释放大量游离血红蛋白(fHb)导致一氧化氮(NO)清除在其中发挥了重要作用。吸入NO可显著降低AKI的发生率，但在以内皮功能障碍为特征的糖脂代谢异常个体，fHb介导的AKI加剧且吸入NO的治疗效果不佳。血管肌内皮连接处NO生物效应受Cyb5R3/Hbα/eNOS调控，申请者预实验发现代谢异常动物Hbα表达上调。提示：代谢障碍时内皮损伤所致Cyb5R3/Hbα/eNOS介导的NO信号调节失常可能是导致肾脏微循环障碍和AKI发生重要机制。本课题拟通过建立离体血管环和小鼠CPB模型，明确Cyb5R3/Hbα/eNOS对NO信号调控在糖脂代谢异常状态下CPB后AKI损伤加重和NO保护效应钝化的机制，为减轻CPB心脏手术后AKI损伤提供新的研究思路与治疗策略。

Acute kidney injury is the most common major complications of cardiac surgery and is independently associated with increased morbidity and mortality. The incidence of cardiac surgery - associated AKI (CSA-AKI) has been reported to be higher than 50%. The development of intravascular hemolysis associated with the use of cardiopulmonary bypass (CPB) is characterized by an acute rise in free hemoglobin. Free hemoglobin potentially causes increased intravascular nitric oxide consumption that limits its bioavailability, which leads to decreasing of renal perfusion, inflammation and oxidative stress. It was demonstrated in our previous studies that administration of nitric oxide by inhalation decreased the incidence of acute kidney injury, transition to stage 3 chronic kidney disease and major adverse kidney events in cardiac surgical patients undergoing prolonged CPB. However, the free hemoglobin mediated AKI was exacerbated while the therapeutic effects of NO inhalation was blunted in animals or in patients with endothelial dysfunction. It was reported that hemoglobin α was expressed and enriched in endothelium cells at the myoendothelial junctions, where Hbα forms complex with Cyb5R3 and eNOS. The Cyb5R3/Hbα/eNOS complex functions to control NO diffusion from the endothelium to the vascular smooth muscle cells by regulating the redox state of the heme in Hbα. In the pilot study, increased Hbα expression was found in HFD and db/db mice with endothelial dysfunction. These findings indicate that the alternation of Cyb5R3/Hbα/eNOS mediated the NO signaling is responsible for impaired renal microcirculation and occurrence of AKI. The current project is aimed to explore the underlying mechanisms of exaggerated AKI and blunted NO therapeutic effects in animals with impaired glucose and lipid metabolism with endothelial dysfunction. The hypothesis that will be testified in this project is that decreased Cyb5R3/Hbα/eNOS mediated NO diffusion and impaired responses to vasodilatory stimuli plays an important role in the development of AKI. Understanding the underlying mechanisms, identifying the high-risk patient populations and exploring an effective method to alleviate the CSA-AKI would be a major advance allowing for better prognosis in patients after CPB assisted cardiac surgery.